The present invention generally relates to a nucleophilic approach for preparing radiolabeled imaging agents. The present invention particularly relates to a nucleophilic approach for preparing radiofluorinated imaging agents which are utilzed in Positron Emission Tomography.
It is estimated there are currently 2–4 million victims of Parkinson's disease (PD) in the United States today. Parkinson's is a progressive irreversible neurodegenerative disease characterized by a loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies. The disease usually strikes during the later years of life, but a significant portion of PD victims develop debilitating symptoms in their highly productive forties or even thirties.
Victims of Parkinson's can present with bradykinesia (slowness and poverty of movement), muscular rigidity, resting tremor (which usually abates during voluntary movement), and an impairment of postural balance leading to disturbances of gait and falling. Without treatment, PD progresses over 5 to 10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism.
Because of its long duration of morbidity (patients usually live 20 years or more under care following onset of symptoms) PD is a disease with major economic and public health impacts in the developed world. The seriousness of this problem is projected to grow over the next 30 years with the approaching demographic bulge of elderly baby-boomers and increase in average age in the populations of North America, Western Europe, and Japan. However, the availability of effective pharmacological treatment has altered radically the prognosis of PD; and in most cases, good functional mobility can be maintained for many years, and the life expectancy of adequately treated patients is substantially increased.
However, in order to optimize the aforementioned pharmacological treatment an early detection and diagnosis of PD must be made. This is particularly evident in light of the fact that current clinical diagnosis, based on PD symptomatology, can only be made after approximately 90% of neurological function in the brain's nigrostriatal dopamine pathway has been lost.
With respect to the early detection and diagnosis of PD, two fluorine-18 labeled tyrosine derivatives, 6-fluoro-dopa (FDOPA) and 6-fluoro-meta-tyrosine (6-FMT), have been demonstrated to be useful PET (positron emission tomography) radiopharmaceuticals for the early diagnosis and study Of PD and related movement disorders in humans. However, there are drawbacks to utilizing the aforementioned fluorine-18 tracers. For example, the fluorine-18 radioisotope only has a two hour halflife and therefore these tracers are typically produced in special cyclotron-PET facilities, and used on-site or within a fairly local distribution radius. In addition, the existing synthetic methods for producing these fluorine-18 tracers are non-routine and commercially unfeasible. As a result of these drawbacks, only a handful of research facilities in the world possess the special equipment or expertise that is currently required to manufacture FDOPA and 6-FMT. Therefore, the clinical use of FDOPA and/or 6-FMT has been limited to perhaps only seven sites in the world at present, i.e. University of Wisconsin, University of California at Berkeley, University of California at Los Angeles, University of British Columbia (Canada), McMaster University (Canada), Universite Libre de Bruxelles (Belgium), and Gunma University (Japan). The limited number of facilities which can clinically utilize FDOPA and/or 6-FMT tracers severely constrains the access PD victims have to these diagnostic tools.
Therefore, in light of the above discussion, it is apparent that what is needed is an approach for preparing radiolabeled imaging agents and associated compounds that addresses one or more of the above discussed drawbacks.